The goal of this project is to develop improved methods for diagnosing and treating ocular inflammatory disease and encompasses both laboratory and clinical studies of uveitis, ocular malignancy, ocular allergy, and inflammatory diseases of the ocular surface. The Clinical Branch laboratory has focused on identifying targets for anti-inflammatory therapy and developing novel ways to deliver these treatments to the eye. We have developed a ragweed-induced murine model of allergic conjunctivitis. Over the past year, we investigated the role of cytokines in development of allergic ocular disease. We demonstrated an exacerbation of ocular inflammation in interferon-gamma and IL-12 knock-out mice. In contrast, IL-4 knock- out mice were resistant to developing ocular allergy, suggesting that ocular conjunctivitis is exacerbated by a lack of Th1 cytokines and inhibited by a lack of Th2 cytokines. We have continued to study the pathogenesis of uveitis. Over the past year, we investigated the effect of costimulation through the interaction of CD40 and CD40 ligand on experimental autoimmune uveitis. Early treatment with a monoclonal antibody against CD40 ligand completely prevented the development of uveitis. Delayed treatment with the anti-CD40 ligand antibody also inhibited disease. Antibody against CD40 ligand also reduced the lymphocyte proliferative response against the immunizing antigen and decreased expression of ICAM-1 in the eye. These data suggest that early costimulation through CD40 ligand is required for the pathogenesis of uveitis and may be a target for anti- inflammatory therapy. Clinical studies have focused on the diagnosis and treatment of uveitis and intraocular lymphoma. The NEI has been investigating the safety and efficacy of oral administration of antigens as a treatment for uveitis. Type II collagen is a possible autoimmune antigen in patients with various forms of rheumatoid arthritis. We are conducting a Phase I/II, open label trial of type II collagen for patients with juvenile rheumatoid arthritis with both joint and eye disease. Recruitment for the study was completed in 1998. Tumor necrosis factor-alpha is a cytokine thought to be involved in the pathogenesis of rheumatoid arthritis in adults and juvenile rheumatoid arthritis in children. A protocol has recently been developed to investigate the effect of a fusion protein of tumor necorisis factor-alpha on the development of eye and joint disease in children with juvenile rheumatoid arthritis. Although corticosteroids remain the mainstay of therapy for intraocular inflammation, many patients are resistant or intolerant of steroid therapy. Other immunosuppressive agents are used to treat sight- threatening ocular inflammatory disease, but these agents are also associated with prominent adverse effects. The Clinical Branch is developing ways to locally deliver drugs into the eye to avoid systemic side effects. The Clinical Branch at the National Eye Institute, in collaboration with Duke University, is currently conducting a Phase I study of a sustained-release intravitreal cyclosporine implant for patients with severe uveitis. Sustained- release implants that release other immunosuppressive agents are also being developed. The Clinical Branch is also studying local administration of antineoplastic agents for intraocular lymphoma. Previous studies conducted in collaboration with the National Cancer Institute showed that ocular recurrence of lymphoma is common in patients treated with systemic andintrathecal chemotherapy. Clinical studies are now investigating the use of intravitreal injections of methotrexate in combination with periocular corticosteroids for recurrent intraocular lymphoma. Studies of intravitreal sustained-release implants to deliver antineoplastic agents for ocular malignancyare planned. Finally, in collaboration with the Pharmaceutical Development Section of the Clinical Center Pharmacy, we are developing sustained-release implants for angiostatic drugs, including thalidomide, for the treatmentof neovascularization of the eye. Bothtoxicity testing and efficacy studies arein progress. These devices may be useful for treating diseases such as age-related macular degeneration.